Westwood, Jessica, India Mayhook-Walker, Ciaran Simpkins, Andrew Darby-Smith, Dan Morris, and Eduardo Normando. Retinal vascular changes in response to hypoxia: a high-altitude expedition study. High Alt Med Biol. 25:49–59, 2024.
Background:
Increased tortuosity and engorgement of retinal vasculature are recognized physiological responses to hypoxia. This can lead to high-altitude retinopathy (HAR), but incidence reports are highly variable, and our understanding of the etiological mechanisms remains incomplete. This study quantitatively evaluated retinal vascular changes during an expedition to 4,167 m.
Methods:
Ten healthy participants summited Mount Toubkal, Morocco. Fundus images were taken predeparture, daily throughout the expedition, and 1 month postreturn. Diameter and tortuosity of four vessels were assessed, in addition to vessel density and features of HAR.
Results:
Significant (p ≤ 0.05) increases in tortuosity and diameter were observed in several vessels on high-altitude exposure days. There was a strong correlation between altitude and supratemporal retinal artery diameter on days 2, 3, and 6 of the expedition (r = 0.7707, 0.7951, 0.7401, respectively; p < 0.05). There was a significant increase in median vessel density from 6.7% at baseline to 10.0% on summit day. Notably there were no incidences of HAR.
Conclusion:
Physiological but not pathological changes were seen in this cohort, which gives insight into the state of the cerebral vasculature throughout this expedition. These results are likely attributable to relatively low altitude exposure, a conservative ascent profile, and the cohort's demographic. Future study must include daily retinal images at higher altitudes and take steps to mitigate environmental confounders. This study is relevant to altitude tourists, patients with diabetic retinopathy or retinal vein occlusion, and critically ill patients.
Get full access to this article
View all access options for this article.
References
1.
AielloLP, AveryRL, ArriggPG, et al.Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med, 1994; 331(22):1480–1487.
2.
AielloLP, NorthrupJM, KeytBA, et al.Hypoxic regulation of vascular endothelial growth factor in retinal cells. Arch Ophthalmol, 1995; 113(12):1538–1544.
3.
AroraR, JhaKN, SathianB. Retinal changes in various altitude illnesses. Singapore Med J, 2011; 52(9):685–688.
4.
BanaeeT, Ansari-AstanehMR, PourrezaH, et al.Utility of 1% tropicamide in improving the quality of images for tele-screening of diabetic retinopathy in patients with dark irides. Ophthalmic Epidemiol, 2017; 24(4):217–221.
BarthelmesD, BoschM, MerzT, et al.Delayed appearance of high altitude retinal haemorrhages. PLoS One, 2011; 6(2):e11532.
7.
BoschMM, MerzTM, BarthelmesD, et al.New insights into ocular blood flow at very high altitudes. J Appl Physiol (1985), 2009; 106(2):454–460.
8.
Brinchmann-HansenO, MyhreK. Blood pressure, intraocular pressure, and retinal vessels after high altitude mountain exposure. Aviat Space Environ Med, 1989; 60(10 Pt 1):970–976.
9.
ButlerFK, HarrisDJ, ReynoldsRD. Altitude retinopathy on Mount Everest, 1989. Ophthalmology, 1992; 99(5):739–746.
10.
BärtschP, BaileyDM. Acute Mountain Sickness and High Altitude Cerebral Oedema. In: High Altitude Human Adaptation to Hypoxia. (Erik S, Peter B. eds.) Springer: New York, NY, 2014; pp. 379–403.
11.
ClarkeAK, CozziM, ImrayCHE, et al.Analysis of retinal segmentation changes at high altitude with and without acetazolamide. Invest Ophthalmol Vis Sci, 2019; 60(1):36–40.
12.
ClarkeC, DuffJ. Mountain sickness, retinal haemorrhages, and acclimatisation on Mount Everest in 1975. Br Med J, 1976; 2(6034):495–497.
13.
Cloud Nine Development. The Eye Handbook. [Mobile app]. 2022. Available from: https://eyehandbook.com/EHBweb/ [Last accessed: March31, 2022].
14.
CourtieE, VeenithT, LoganA, et al.Retinal blood flow in critical illness and systemic disease: A review. Ann Intensive Care, 2020; 10(1):152.
15.
DeloriFC, FitchKA, FekeGT, et al.J. Evaluation of micrometric and microdensitometric methods for measuring the width of retinal vessel images on fundus photographs. Graefes Arch Clin Exp Ophthalmol, 1988; 226(4):393–399.
16.
DornerGT, GarhoferG, KissB, et al.Nitric oxide regulates retinal vascular tone in humans. Am J Physiol Heart Circ Physiol, 2003; 285(2):H631–H636.
17.
FischerMJM, UchidaS, MesslingerK. Measurement of meningeal blood vessel diameter in vivo with a plug-in for ImageJ. Microvasc Res, 2010; 80(2):258–266.
18.
ForresterJ, DickA, McMenaminP, et al.The Eye: Basic Sciences in Practice. Edinburgh: Saunders; 2008.
19.
FrayserR, HoustonCS, BryanAC, et al.Retinal hemorrhage at high altitude. N Engl J Med, 1970; 282(21):1183–1184.
20.
GrimmingerJ, RichterM, TelloK, et al.Thin air resulting in high pressure: mountain sickness and hypoxia-induced pulmonary hypertension. Can Respir J, 2017; 2017:8381653.
21.
HackettPH, RennieD. Rales, peripheral edema, retinal hemorrhage and acute mountain sickness. Am J Med, 1979; 67(2):214–218.
22.
HaefligerIO, MeyerP, FlammerJ, et al.The vascular endothelium as a regulator of the ocular circulation: A new concept in ophthalmology?. Surv Ophthalmol, 1994; 39(2):123–132.
23.
HartWE, GoldbaumM, CôtéB, et al.Measurement and classification of retinal vascular tortuosity. Int J Med Inform, 1999; 53(2–3):239–252.
24.
HayrehSS, ServaisGE, VirdiPS, et al.Fundus lesions in malignant hypertension: III. Arterial blood pressure, biochemical, and fundus changes. Ophthalmology, 1986; 93(1):45–59.
25.
HonigmanB, NoordewierE, KleinmanD, et al.High altitude retinal hemorrhages in a Colorado skier. High Alt Med Biol, 2001; 2(4):539–544.
26.
HoustonCS, McFaddenM. Long-term effects of altitude on the eye. Lancet, 1979; 8132:49.
27.
InvernizziA, TorreA, ParrulliS, et al.Retinal findings in patients with COVID-19: Results from the SERPICO-19 study. EClinicalMedicine, 2020; 27:100550.
28.
KaushikS, KifleyA, MitchellP, et al.Age, blood pressure, and retinal vessel diameter: Separate effects and interaction of blood pressure and age. Invest Ophthalmol Vis Sci, 2007; 48(2):557–561.
29.
KimJ, MontagnaniM, KohKK, et al.Reciprocal relationships between insulin resistance and endothelial dysfunction. Circulation, 2006; 113(15):1888–1904.
30.
KnudtsonMD, KleinBEK, KleinR, et al.Variation associated with measurement of retinal vessel diameters at different points in the pulse cycle. Br J Ophthalmol, 2004; 88:57–61.
31.
KramárPO, DrinkwaterBL, FolinsbeeLJ, et al.Ocular functions and incidence of acute mountain sickness in women at altitude. Aviat Space Environ Med, 1983; 54(2):116–120.
32.
MacCormickI, SomnerJ, MorrisD, et al.Retinal vessel tortuosity in response to hypobaric hypoxia. High Alt Med Biol, 2012; 13(4):263–268.
33.
MagalhãesJ, AscensãoA, SoaresJM, et al.Acute and severe hypobaric hypoxia increases oxidative stress and impairs mitochondrial function in mouse skeletal muscle. J Appl Physiol (1985), 2005; 99(4):1247–1253.
34.
MastyuginV, MosaedS, BonazziA, et al.Corneal epithelial VEGF and cytochrome P450 4B1 expression in a rabbit model of closed eye contact lens wear. Curr Eye Res, 2001; 23(1):1–10.
35.
McFaddenDM, HoustonCS, SuttonJR, et al.High-altitude retinopathy. JAMA, 1981; 245(6):581–586.
36.
MorrisD, MellaS, DeplaD. Eye problems on expeditions. Travel Med Infect Dis, 2013; 11(3):152–158.
37.
MorrisD, SomnerJ, DonaldM, et al.The Eye at Altitude. In: Hypoxia and Exercise. (Roach R, Wagner P, Hackett P. eds.) Springer Publishers: New York, NY; 2006; pp. 249–271.
38.
MukhtarA, KhanMS, HabibA, et al.Visual outcome of retinal vein occlusion in patients residing at high altitude. J Pak Med Assoc, 2017; 67(5):735–738.
39.
Müllner-EidenböckA, RainerG, StrennK. et al. High-altitude retinopathy and retinal vascular dysregulation. Eye (Lond), 2000; 14(Pt 5):724–729.
40.
NagaokaT, SakamotoT, MoriF, et al.The effect of nitric oxide on retinal blood flow during hypoxia in cats. Invest Ophthalmol Vis Sci, 2002; 43(9):3037–3044.
41.
NewsomRS, SullivanPM, RassamSM, et al.Retinal vessel measurement: Comparison between observer and computer driven methods. Graefes Arch Clin Exp Ophthalmol, 1992; 230(3):221–225.
42.
PattonN, AslamT, MacgillivrayT, et al.Retinal vascular image analysis as a potential screening tool for cerebrovascular disease: A rationale based on homology between cerebral and retinal microvasculatures. J Anat, 2005; 206(4):319–348.
43.
PopelAS, JohnsonPC. Microcirculation and hemorheology. Annu Rev Fluid Mech, 2005; 37:43–69.
44.
RajaW, MukhtarA. High altitude retinopathy presenting as central retinal vein occlusion in a soldier. J Coll Physicians Surg Pak, 2017; 27(12):780–782.
RoachRC, HackettPH, OelzO, et al.The 2018 Lake Louise acute mountain sickness score. High Alt Med Biol, 2018; 19(1):4–6.
47.
RuanS, LiuY, HuWT, et al.A new handheld fundus camera combined with visual artificial intelligence facilitates diabetic retinopathy screening. Int J Ophthalmol, 2022; 15(4):620–627.
48.
SagooRS, HutchinsonCE, WrightA, et al.Magnetic resonance investigation into the mechanisms involved in the development of high-altitude cerebral edema. J Cereb Blood Flow Metab, 2017; 37(1):319–331.
49.
SchindelinJ, Arganda-CarrerasI, FriseE, et al.Fiji: An open-source platform for biological-image analysis. Nat Methods, 2012; 9(7):676–682.
50.
SchmettererL, PolakK. Role of nitric oxide in the control of ocular blood flow. Prog Retin Eye Res, 2001; 20(6):823–847.
51.
SchneiderCA, RasbandWS, EliceiriKW. NIH Image to ImageJ: 25 Years of image analysis. Nat Methods, 2012; 9(7):671–675.
52.
SchumacherGA, PetajanJH. High altitude stress and retinal hemorrhage: Relation to vascular headache mechanisms. Arch Environ Health, 1975; 30(5):217–221.
53.
ShoE, NanjoH, ShoM, et al.Arterial enlargement, tortuosity, and intimal thickening in response to sequential exposure to high and low wall shear stress. J Vasc Surg, 2004; 39(3):601–612.
54.
ShultsWT, SwanKC. High altitude retinopathy in mountain climbers. Arch Ophthalmol, 1975; 93(6):404–408.
55.
SinghI, KhannaPK, SrivastavaMC, et al.Acute mountain sickness. N Engl J Med, 1969; 280(4):175–184.
56.
SunC, WangJJ, MackeyDA, et al.Retinal vascular caliber: systemic, environmental, and genetic associations. Surv Ophthalmol, 2009; 54(1):74–95.
57.
TianX, ZhangB, JiaY, et al.Retinal changes following rapid ascent to a high-altitude environment. Eye (Lond), 2018; 32(2):370–374.
58.
TingayDG, TsimnadisP, BasnyatB. A blurred view from Everest. Lancet, 2003; 362(9400):1978.
59.
WalterR, MaggioriniM, ScherrerU, et al.Effects of high-altitude exposure on vascular endothelial growth factor levels in man. Eur J Appl Physiol, 2001; 85(1–2):113–117.
60.
WiedmanM. High altitude retinal hemorrhage. Arch Ophthalmol, 1975; 93(6):401–403.
WillmannG, FischerMD, SchommerK, et al.Missing correlation of retinal vessel diameter with high-altitude headache. Ann Clin Transl Neurol, 2014; 1(1):59–63.
63.
WillmannG, SchatzA, GekelerF, et al.Estimated incidence of high altitude retinal hemorrhages. Graefes Arch Clin Exp Ophthalmol, 2018; 256(1):231–232.
64.
WilsonMH, DavagnanamI, HollandG, et al.Cerebral venous system and anatomical predisposition to high-altitude headache. Ann Neurol, 2013; 73(3):381–389.
65.
World Medical Association. World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. JAMA, 2013; 310(20):2191–2194.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
